Glial cells participate in the local immune response in the central nervous system (CNS) as antigen presenting cells (APC) by acquiring moleculs of the major histocompatibility complex (MHC) not normally expressed in vivo. Thus, induction of MHC molecules on glial cells directly by virus or cytokines could initiate immune responses in the CNS by allowing these cells to present viral or autoantigen to T-cells, or become targets for cytotoxic T-cells (CTL). Recently we have demonstrated that primary adult human glial cells (AHGC) and atrocytic cell lines expressing MHC class I and class II molecules can process and present viral and autoantigen to CTL in an antigen-specific and MHC-restricted fashion. The purpose of this application is to examine the regulation and function of MHC class II molecules on AHGC in response to measles virus (MV) with emphasis on the microglia as a potential as a potential APC in the CNS. First, we will determine whether differences in the inducibility of MHC class II molecules exist among primary microglia, astrocytes and oligodendrocytes in response to MV. This is of importance as it dictates the capacity of these cells to present antigen and to be lysed by CTL. We will also investigate the cellular mechanisms for MV upregulation of MHC class II molecules and identify enhancer elements in the class II DRalpha gene that confer response to MV using a glioblastoma multiform cell line. Second, we will examine he functional significance of class II upregulation in the CNS with emphasis on the microglia as a potential APC. This will be examined in vitro by comparing the capacity of primary human microglia and peripheral blood macrophages to process and present viral and autoantigen to T-cell lines; to activate an antigen-specific T-cell response from resting peripheral blood lymphocytes, and to function as targets for CTL. MV and myelin basic protein will be used as antigens to address these questions.
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